title: Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP.
abstract: Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs. The cross-talk between the two major pathways-one mediated by cAMP and the other by EFAs-paves the way to new approaches to understand and control pain.
authors.affiliation: Department of Entomology and University of California Davis Cancer Center, School of Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.forename: Karen
authors.initials: K
authors.lastname: Wagner
authors.forename: Nils H
authors.initials: NH
authors.lastname: Schebb
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Steven L
authors.initials: SL
authors.lastname: Jinks
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.forename: Christine
authors.initials: C
authors.lastname: Hegedus
authors.forename: Tristan
authors.initials: T
authors.lastname: Rose
authors.forename: Robert
authors.initials: R
authors.lastname: Brosnan
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000378:metabolism; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects*
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004851:Epoxide Hydrolases